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Monitoring Molecules in Neuroscience Then and Now Margaret E. Rice* Department of Neurosurgery and Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016 United States ABSTRACT: The 16th International Conference on Monitoring Molecules in Neuroscience (MMiN) was held in Gothenburg, Sweden in late spring 2016. This conference originated as a methods meeting focused on in vivo voltammetric techniques and microdialysis. Over time, however, the scope has evolved to include a number of other methods for neurochemical detection that range from single-cell fluorescence in vitro and in vivo in animal models to whole-brain imaging in humans. Overall, MMiN provides a unique forum for introducing new developments in neurochemical detection, as well as for reporting exciting neurobiological insights provided by established and novel methods. This Viewpoint includes a brief history of the meeting, factors that have contributed its evolution, and some highlights of MMiN 2016. KEYWORDS: Analytical methods, brain slices, fluorescence imagining, microdialysis microelectrodes, in vivo, voltammetry
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he 16th International Conference on Monitoring Molecules in Neuroscience (MMiN) was held in Gothenburg, Sweden from May 29 to June 2, 2016, and was co-chaired by Andrew Ewing and Ann-Sofie Cans. MMiN 2016 was sponsored by the International Society for Monitoring Molecules in Neuroscience (http://www.monitoringmolecules. org/) and was attended by 259 scientists from 21 countries and 5 continents: Europe, North America, South America, Asia, and Australia. The list of attendees included scientists from academia and industry, clinicians, and a number of postdoctoral fellows, graduate students, and undergraduates. A word cloud illustrating the relative frequency of words in the MMiN 2016 program reflects the home institutions of attendees, methods used, species studied, as well as the names of the organizers, session chairs, speakers, and sponsors (Figure 1). This representation gives a surprisingly good sense of the meeting and its complex components. Historically, this biennial conference was known as the “In Vivo Meeting”, the official name of which was The International Conference on In Vivo Methods. As regular attendees know, the first meeting was Nottingham, U.K. in 1982, and was organized by Charles Marsden to bring together investigators in the new fields of in vivo microdialysis and in vivo voltammetry. Both methods provided new insights into brain function and were practiced by Prof. Marsden. The report that introduced voltammetry as a “new neurophysiological measurement” was published in 1973 by Ralph Adam’s group1 shortly before the first report from Urban Ungerstedt’s group2 on the use of in vivo microdialysis to detect amphetamine-induced release of 3 H-dopamine. Electrochemical detection, also developed by the Adams group,3 when combined with microdialysis enabled detection of endogenous dopamine and other electroactive substances. Voltammetry and microdialysis have complementary strengths and limitations (reviewed recently4). Voltammetric methods provide rapid (subsecond), direct detection of electroactive substances including dopamine, serotonin, hydrogen peroxide (H2O2), and adenosine with micrometer spatial resolution (carbon-fiber microelectrodes can be 200 μm in diameter, >500 μm length), and longer sampling times, usually 5−20 min, although times as short as 5 s have been reported.5 These methods have continued to evolve, with refinements over the past decade that have led to a resurgence in the popularity and utility of both. Which method is best? The decision depends on the specific questions addressed. For example, monitoring spontaneous or stimulated dopamine transients in the brain extracellular space requires a fast detection method like fast-scan cyclic voltammetry (FSCV) or amperometry. Indeed, studies in which optogenetic methods are used to examine the role of dopamine in specific behaviors or disease models nearly universally use FSCV to confirm lightactivated dopamine release when channelrhodopsin is expressed selectively in dopaminergic neurons. On the other hand, microdialysis is well-suited for monitoring extracellular glucose and lactate concentrations simultaneously over many minutes. A striking use of microdialysis is at the bedside in patients, for example, after a stroke, which provides novel clinical insights. The change of the original name of the International Conference on In Vivo Methods to Monitoring Molecules in Neuroscience not only emphasized its focus on neuroscience, but also reflected two changes in the landscape of the field. First, although the introduction of new methods remains a core theme of the meeting, this aspect of the conference has broadened to include novel uses of existing methodsand more significantly, new findings obtained with these and other methods. This shift reflects the widespread acceptance of neurochemical methods as part of the current neuroscience tool kit. For example, a PubMed search for the reported use of in vivo voltammetric methods [amperometry, voltammetry, chronoamperometry, etc. AND brain OR intracerebral, etc. AND in vivo OR freely moving OR awake OR anesthetized] reveals that, from 1974 to 1996, 541 reports were published with abstracts indicating the use of an in vivo voltammetric method in the brain; 52% included the method in the title. From 1997 to 2017, the number of publications reporting in vivo voltammetry rose to 741, but only 21% of the titles indicated the method. An analogous search to capture these parameters for in vivo microdialysis shows more widespread use of this technique compared to in vivo voltammetry, with 1975 reports in the 1974−1996 period mentioning microdialysis in their abstracts, 37% of which included this key word in the title. Over the next 20 years, 1997−2017, the number of microdialysis studies more than doubled with 4757 publications listed in PubMed, although the title indicated the method in only 21% of these. The second aspect of the changing scientific landscape that motivated the update to MMiN was the increasing reliance on in vitro preparations for methods development and use, including ex vivo brain slices, dissociated neurons, neuronal and glial cultures, and other cells and cell lines. A PubMed search for the use of a voltammetric method in brain slices or other in vitro neuronal preparation indicates 165 publications from 1974 to 1996, but 500 from 1997−2017, which B
DOI: 10.1021/acschemneuro.7b00043 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience demonstrated the value of voltammetric methods and microdialysis for studying dynamic transmitter release in specific behaviors or disease models and slower neurochemical changes that reflect changes in metabolic state. However, these were from the only tools utilized, as seen in the array of data obtained using cutting-edge methods, like fluorescence imaging in vivo and in vitro, whole-brain imaging with increasing specificity and resolution, and ever-smaller and faster biosensors that gain molecular specificity through incorporation of antibodies or ion channels. Thus, MMiN remains a unique and relevant forum for introducing new developments in neurochemical detection, as well as for reporting exciting neurobiological insights provided by established and novel methods.
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AUTHOR INFORMATION
Corresponding Author
*Mailing address: Department of Neuroscience and Physiology and New York University School of Medicine 550 First Avenue New York, NY 10016. Phone: 212-263-5438. Fax: 212-6890334. E-mail:
[email protected]. ORCID
Margaret E. Rice: 0000-0003-1793-2798 Funding
Research in the Rice laboratory is supported by NIH/NIDA Grants R01 DA033811 and R01 DA038616 and the NYU Fresco Institute for Parkinson’s and Movement Disorders. Notes
The author declares no competing financial interest.
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REFERENCES
(1) Refshauge, C., Kissinger, P. T., Dreiling, R., Blank, L., Freeman, R., and Adams, R. N. (1974) New high performance liquid chromatographic analysis of brain catecholamines. Life Sci. 14, 311− 322. (2) Ungerstedt, U., and Pycock, C. (1974) 3H-dopamine recovered during the administration of amphetamine. Bull. Schweiz. Akad. Med. Wiss. 1278, 1−13. (3) Kissinger, P. T., Hart, J. B., and Adams, R. N. (1973) Voltammetry in brain tissue − A new neurophysiological measurement. Brain Res. 55, 209−213. (4) Kehr, J., and Yoshitake, T. (2013) Monitoring molecules in neuroscience: Historical overview and current advancements. Front. Biosci., Elite Ed. 5, 947−954. (5) Lada, M. W., Vickroy, T. W., and Kennedy, R. T. (1998) Evidence for neuronal origin and metabotropic receptor-mediated regulation of extracellular glutamate and aspartate in rat striatum in vivo following electrical stimulation of the prefrontal cortex. J. Neurochem. 70, 617−625. (6) Rice, M. E., Patel, J. C., and Cragg, S. J. (2011) Dopamine release in the basal ganglia. Neuroscience 198, 112−137.
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DOI: 10.1021/acschemneuro.7b00043 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
